CA2748392C - Use of interleukin-22 for the prevention and/or treatment of multiple organ dysfunction syndrome (mods) - Google Patents
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- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/19—Cytokines; Lymphokines; Interferons
- A61K38/20—Interleukins [IL]
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Abstract
The present invention relates to use an agent for the prevention and/or treatment of multiple organ dysfunction syndrome (MODS) or multiple organ failure (MOF) comprising interleukin-22 (IL-22) as an effective ingredient. The present invention is applicable to prevention of or therapy for diseases from sepsis, septic shock, liver failure, to multiple organ dysfunction syndromes. More particularly, the present invention is useful for an emergency medical service, for treatment of injury caused by a traffic accident, burns, heat attacks, hypercytokinemia or severe infective diseases.
Description
2 PCT/US2010/020673 Use of Interleukin-22 for the prevention and/or treatment of multiple organ dysfunction syndrome (MODS) FIELD OF INVENTION
[0001] This invention relates to the medical use of Interleukin-22 (IL-22).
BACKGROUND OF INVENTION
[0002] Multiple organ dysfunction syndrome (MODS), previously known as multiple organ failure (MOF), is altered organ function in an acutely ill patient such that homeostasis cannot be maintained without medical intervention. It is well established that Systemic Inflammatory Response Syndrome (SIRS) will lead to sepsis or severe sepsis and eventually lead to MODS. MODS usually results from uncontrolled inflammatory response which is triggered by infection, injury (accident or surgery), hypoperfusion and/or hypermetabolism. The uncontrolled inflammatory response will lead to SIRS or sepsis.
[0001] This invention relates to the medical use of Interleukin-22 (IL-22).
BACKGROUND OF INVENTION
[0002] Multiple organ dysfunction syndrome (MODS), previously known as multiple organ failure (MOF), is altered organ function in an acutely ill patient such that homeostasis cannot be maintained without medical intervention. It is well established that Systemic Inflammatory Response Syndrome (SIRS) will lead to sepsis or severe sepsis and eventually lead to MODS. MODS usually results from uncontrolled inflammatory response which is triggered by infection, injury (accident or surgery), hypoperfusion and/or hypermetabolism. The uncontrolled inflammatory response will lead to SIRS or sepsis.
[0003] SIRS is an inflammatory state affecting the whole body. It is one of several conditions related to systemic inflammation, organ dysfunction, and organ failure. SIRS
is a subset of cytokine storm, in which there is abnormal regulation of various cytokines.
The cause of SIRS can be classified as infectious or noninfectious. SIRS is also closely related to sepsis. When SIRS is due to an infection, it is considered as sepsis.
Noninfectious causes of SIRS include trauma, burns, pancreatitis, ischemia and hemorrhage. Sepsis is a serious medical condition characterized by a whole-body inflammatory state. Sepsis can lead to septic shock, multiple organ dysfunction syndrome and death. Both SIRS and sepsis could ultimately progress to MODS.
is a subset of cytokine storm, in which there is abnormal regulation of various cytokines.
The cause of SIRS can be classified as infectious or noninfectious. SIRS is also closely related to sepsis. When SIRS is due to an infection, it is considered as sepsis.
Noninfectious causes of SIRS include trauma, burns, pancreatitis, ischemia and hemorrhage. Sepsis is a serious medical condition characterized by a whole-body inflammatory state. Sepsis can lead to septic shock, multiple organ dysfunction syndrome and death. Both SIRS and sepsis could ultimately progress to MODS.
[0004] The underline mechanism of MODS is not well understood. At present there is no agent that can reverse the established organ failure. Therapy therefore is limited to SUBSTITUTE SHEET (RULE 26) supportive care. Prevention and treatment for MODS, MOF or sepsis are important to emergency medical service, for treatment of injury caused by traffic accident, burns, heart attacks, and severe infective diseases. Therefore, the development of an effective drug is in urgent need for patients.
SUMMARY OF INVENTION
SUMMARY OF INVENTION
[0005] It is therefore an object of the present invention to provide a therapeutic composition and method for MODS, MOF or sepsis.
[0006] Accordingly, the present invention, in one aspect, provides the use of interleukin-22 (IL-22) in manufacture of a composition for preventing and/or treating MODS, MOF, sepsis, or liver failure.
[0007] In another aspect, the present invention provides a method for the prevention and the treatment of MODS, MOF, sepsis, or liver failure in a subject, the method comprising administering a pharmaceutically effective amount of IL-22. In a further aspect, the present invention relates to the use of IL-22 in the manufacture of a medicament for preventing and treating MODS, MOF, sepsis, or liver failure. MODS, MOF or sepsis may be caused by, among other causes, trauma such as traffic accidents, burns, heart attack, and severe infective diseases.
[0008] In various aspects, IL-22 of the present invention includes but is not limited to mammal IL-22 and recombinant mammal IL-22. In a preferred embodiment, IL-22 is human IL-22.
BRIEF DESCRIPTION OF FIGURES
BRIEF DESCRIPTION OF FIGURES
[0009] Figure lshows the Murine interleukin-22 cDNA sequence.
[0010] Figure 2 shows the Human interleukin-22 cDNA sequence.
SUBSTITUTE SHEET (RULE 26)
SUBSTITUTE SHEET (RULE 26)
[0011] Figure 3 shows the Murine interleukin-22 amino acid sequence.
[0012] Figure 4 shows the Human interleukin-22 amino acid sequence.
[0013] Figure 5 shows that IL-22 increased animal survival in LPS-induced sepsis shock in mice.
[0014] Figure 6 shows that IL-22 protects LPS-induced multiple organ failure in rats caused by cachexia.
[0015] Figure 7 shows that IL-22 protected animal from death in LPS/GaIN-induced acute liver failure in mice.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0016] Example 1: Human and murine IL-22 gene cloning
[0017] Cloning of human IL-22 gene: Human peripheral blood monocytes were stimulated with anti-human CD3 mAb and cultured for 24 h. Total RNA was extracted by ultracentrifugation, and cDNA was synthesized with the d'I' primers. Human 11,22 gene was amplified by PCR with the sense primer (5'-GCA GAA TCT TCA GAA CAG GTT
C-3') and anti-sense primer (5'-GGC ATC TAA TTG TTA TTT CTA G-3'). The amplified DNA is cloned into E.coli expression vector.
C-3') and anti-sense primer (5'-GGC ATC TAA TTG TTA TTT CTA G-3'). The amplified DNA is cloned into E.coli expression vector.
[0018] Cloning of mouse IL-22 gene: C57BL/6 female mice were injected with LPS
(5 mg/kg, sc). The spleen was obtained after 20 hours. Total RNA was extracted and cDNA
was synthesized with the dT primers. Mouse IL-22 gene was amplified by PCR
with the sense primer (5'-CTC TCA CTT ATC AAC TGT TGA C-3') and anti-sense primer (5'-GAT GAT GGA CGT TAG CTT CTC AC-3'). The amplified eDNA was cloned into E.coli expression vector pE,T21(+)
(5 mg/kg, sc). The spleen was obtained after 20 hours. Total RNA was extracted and cDNA
was synthesized with the dT primers. Mouse IL-22 gene was amplified by PCR
with the sense primer (5'-CTC TCA CTT ATC AAC TGT TGA C-3') and anti-sense primer (5'-GAT GAT GGA CGT TAG CTT CTC AC-3'). The amplified eDNA was cloned into E.coli expression vector pE,T21(+)
[0019] Both human IL-22 and murine IL-22 were verified by DNA sequencing, as shown in Fig. 1 and Fig.2.
SUBSTITUTE SHEET (RULE 26) [00201 Example 2: human IL-22 and mouse IL-22 gene expression [0021 ] E. coli strain BI,21(+) was used to express the recombinant protein.
The E.coli cells were homogenized under high pressure. IL-22 inclusion bodies were obtained by centrifugation and washed with buffers (Tris-HC1 50 mM, NaCl 100 mM, EDTA 1 mM, DTT 1 mM, and sodium deoxycholate 0.5%) completely. Inclusion bodies were solubilized in 8M urea, 50 mM Mes, 10 mM EDTA, and 0.1 mM DTT, pH 6.5.
Inclusion bodies was refolded 4 times for 20 hours in 100 mM Tris-HC1, 2 mM EDTA, 0.5 M
L-arginine, 1 mM reduced glutathion, and 0.1mM oxidized glutathion, pH 8. The mixture was then concentrated and purified using a Superdex75 (Amersham) column chromatography. The protein was eluted with 20 mM Tris-HCI, 50 mM NaCl, pH 7.
The purity of IL-22 was determined by SDS-PAGE (>95%) as shown in Fig.3 and Fig.4.
IL-22 protein aliquot was stored at -80 C.
[00221 Example 3: Protective Effect of IL-22 on Endotoxin-induced sepsis in mice [0023] Female Balb/c mice, at 6 to 8 weeks, were treated with lipopolysacchride (LPS, salmonella abortus-equi (L-5886, Sigma) prepared at 1.0 mg/mL saline. 0.2 mL
LPS
solution was injected by i.p. to mice at dose of 10 mg/kg. Animals were divided to different treatment groups and survival was monitored for 7 days. Single dose of LPS at >12.0 mg/kg could result in 100% animal death at 48 to 72 hrs. LPS dosed at 10 mg/kg single dose resulted in 20 to 30% animal survival by day 7.
[0024] Treatment of mice started with daily subcutaneous injection of recombinant mouse IL-22, at 100 ug/kg, and 500 ug/kg. Control mice were treated with carrier, 0.5%
BSA and saline. Results are shown in Fig 5. Control mice (carrier, n=10) had
SUBSTITUTE SHEET (RULE 26) [00201 Example 2: human IL-22 and mouse IL-22 gene expression [0021 ] E. coli strain BI,21(+) was used to express the recombinant protein.
The E.coli cells were homogenized under high pressure. IL-22 inclusion bodies were obtained by centrifugation and washed with buffers (Tris-HC1 50 mM, NaCl 100 mM, EDTA 1 mM, DTT 1 mM, and sodium deoxycholate 0.5%) completely. Inclusion bodies were solubilized in 8M urea, 50 mM Mes, 10 mM EDTA, and 0.1 mM DTT, pH 6.5.
Inclusion bodies was refolded 4 times for 20 hours in 100 mM Tris-HC1, 2 mM EDTA, 0.5 M
L-arginine, 1 mM reduced glutathion, and 0.1mM oxidized glutathion, pH 8. The mixture was then concentrated and purified using a Superdex75 (Amersham) column chromatography. The protein was eluted with 20 mM Tris-HCI, 50 mM NaCl, pH 7.
The purity of IL-22 was determined by SDS-PAGE (>95%) as shown in Fig.3 and Fig.4.
IL-22 protein aliquot was stored at -80 C.
[00221 Example 3: Protective Effect of IL-22 on Endotoxin-induced sepsis in mice [0023] Female Balb/c mice, at 6 to 8 weeks, were treated with lipopolysacchride (LPS, salmonella abortus-equi (L-5886, Sigma) prepared at 1.0 mg/mL saline. 0.2 mL
LPS
solution was injected by i.p. to mice at dose of 10 mg/kg. Animals were divided to different treatment groups and survival was monitored for 7 days. Single dose of LPS at >12.0 mg/kg could result in 100% animal death at 48 to 72 hrs. LPS dosed at 10 mg/kg single dose resulted in 20 to 30% animal survival by day 7.
[0024] Treatment of mice started with daily subcutaneous injection of recombinant mouse IL-22, at 100 ug/kg, and 500 ug/kg. Control mice were treated with carrier, 0.5%
BSA and saline. Results are shown in Fig 5. Control mice (carrier, n=10) had
20%
survival by day 7. Treatment of IL-22 at 100 ug/kg and 500 ug/kg resulted in significant animal survival. These results show that IL-22 significantly protect mice from death in LPS-induced sepsis shock model.
[0025] Example 4: Protective Effect of IL-22 on Endotoxin-induced multiple organ failure in rats.
SUBSTITUTE SHEET (RULE 26) [0026] Animal model of multiple organ failure was established by daily injection of endotoxin (LPS-E-coli; 10 mg/kg/day, Difco) to 6 weeks old male Wister rats.
Animals were divided into different treatment groups (n=8). Recombinant mouse IL-22 was administered subcutaneously at 100, 300, and 1000 ug/kg/day daily for 7 days.
Control animals were injected with carrier solution only, 0.5% BSA PBS, pH7Ø Serum protein and albumin levels were measured at the end of 7 day treatment.
[0027] Results are shown in Fig 6. Serum levels of total proteins, albumin were decreased in control group, indicating that these rats were suffering from cachexia.
Animals treated with rmlL-22 had significantly improved blood chemistry parameters. 'These data shows that IL-22 was effective in protect multiple organ failure in rats caused by endotoxin-induced cachexia.
[0028] Example 5: Protective Effect of IL-22 on LPS/GaIN-induced acute liver failure in mice.
[0029] Lippolysaccharides (LPS, 100 ng/mL, Sigma, Cat: L2630) and D-galactosamine (D-Ga1N, 130 mg/mL, Sigma, Cat: G1639) were prepared in pyrogen-free saline.
Female BALB/c mice, 6-8 weeks, were injected introperitoneally (i.p.) with 0.2mL
solution containing 0.ImL of I,PS and 0.1 ml, D-GaIN. The injection of LPS/Ga1N into mice induced acute liver failure evidenced by rapid elevation of liver enzymes (>
20-fold increase compared to control group) including a greater than 20-fold increase of alanine aminotransferase (ALT) and a greater than 40-fold increase of aspartate aminotransferase (AST) in the serum at 8 hrs. Less than 20% mice were viable at 24 hrs after LPS/Ga1N
challenge.
[0030] Treatment of mice started with subcutaneous injection of recombinant mouse IL-22, at 100 ug/kg, and 300 ug/kg. Control mice were treated with carrier, 0.5%
BSA and saline. Results are shown in Fig 7. Control mice (carrier, n=10) had 12.5%
survival at 16 hrs. Treatment of IL-22 at 100 ug/kg and 300 ug/kg resulted 37.5% and 62.5%
(n=10) survival, respectively. These results show that IL-22 significantly protect mice from LPS/GaIN induced death mainly resulted from acute liver failure.
SUBSTITUTE SHEET (RULE 26)
survival by day 7. Treatment of IL-22 at 100 ug/kg and 500 ug/kg resulted in significant animal survival. These results show that IL-22 significantly protect mice from death in LPS-induced sepsis shock model.
[0025] Example 4: Protective Effect of IL-22 on Endotoxin-induced multiple organ failure in rats.
SUBSTITUTE SHEET (RULE 26) [0026] Animal model of multiple organ failure was established by daily injection of endotoxin (LPS-E-coli; 10 mg/kg/day, Difco) to 6 weeks old male Wister rats.
Animals were divided into different treatment groups (n=8). Recombinant mouse IL-22 was administered subcutaneously at 100, 300, and 1000 ug/kg/day daily for 7 days.
Control animals were injected with carrier solution only, 0.5% BSA PBS, pH7Ø Serum protein and albumin levels were measured at the end of 7 day treatment.
[0027] Results are shown in Fig 6. Serum levels of total proteins, albumin were decreased in control group, indicating that these rats were suffering from cachexia.
Animals treated with rmlL-22 had significantly improved blood chemistry parameters. 'These data shows that IL-22 was effective in protect multiple organ failure in rats caused by endotoxin-induced cachexia.
[0028] Example 5: Protective Effect of IL-22 on LPS/GaIN-induced acute liver failure in mice.
[0029] Lippolysaccharides (LPS, 100 ng/mL, Sigma, Cat: L2630) and D-galactosamine (D-Ga1N, 130 mg/mL, Sigma, Cat: G1639) were prepared in pyrogen-free saline.
Female BALB/c mice, 6-8 weeks, were injected introperitoneally (i.p.) with 0.2mL
solution containing 0.ImL of I,PS and 0.1 ml, D-GaIN. The injection of LPS/Ga1N into mice induced acute liver failure evidenced by rapid elevation of liver enzymes (>
20-fold increase compared to control group) including a greater than 20-fold increase of alanine aminotransferase (ALT) and a greater than 40-fold increase of aspartate aminotransferase (AST) in the serum at 8 hrs. Less than 20% mice were viable at 24 hrs after LPS/Ga1N
challenge.
[0030] Treatment of mice started with subcutaneous injection of recombinant mouse IL-22, at 100 ug/kg, and 300 ug/kg. Control mice were treated with carrier, 0.5%
BSA and saline. Results are shown in Fig 7. Control mice (carrier, n=10) had 12.5%
survival at 16 hrs. Treatment of IL-22 at 100 ug/kg and 300 ug/kg resulted 37.5% and 62.5%
(n=10) survival, respectively. These results show that IL-22 significantly protect mice from LPS/GaIN induced death mainly resulted from acute liver failure.
SUBSTITUTE SHEET (RULE 26)
Claims (7)
1. Use of IL-22 in the manufacture of a composition for preventing and/or treating multiple organ dysfunction syndromes in a subject.
2. The use of claim 1 wherein said IL-22 increases serum total protein in said subject suffering multiple organ dysfunction syndromes.
3. The use of claim 1 wherein said IL-22 increases serum albumin in said subject suffering multiple organ dysfunction syndromes.
4. The use of claim 1 wherein said IL-22 is mammal IL-22.
5. The use of claim 1 wherein said IL-22 is recombinant mammal IL-22.
6. The use of claim 1 wherein a pharmaceutically effective amount of said ranges from 100 to 1000 micrograms per kilogram of said subject per day.
7. A composition for prevention or treatment of multiple organ dysfunction syndromes in a subject comprising IL-22 and pharmaceutically acceptable carriers.
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| US14413409P | 2009-01-12 | 2009-01-12 | |
| US61/144,134 | 2009-01-12 | ||
| PCT/US2010/020673 WO2010081112A1 (en) | 2009-01-12 | 2010-01-11 | Prevention and/or treatment of multiple organ dysfunction syndrome with interleukin-22 |
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| CA2748392C true CA2748392C (en) | 2017-06-27 |
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| EP (1) | EP2385841B1 (en) |
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| CN101361968B (en) | 2007-08-06 | 2011-08-03 | 健能隆医药技术（上海）有限公司 | Use of interleukin-22 in treating fatty liver |
| EP3385277A1 (en) | 2013-03-15 | 2018-10-10 | F. Hoffmann-La Roche AG | Il-22 polypeptides and il-22 fc fusion proteins and methods of use |
| CN104623637A (en) | 2013-11-07 | 2015-05-20 | 健能隆医药技术（上海）有限公司 | Application of IL-22 dimer in preparation of intravenous injection drugs |
| WO2017181143A1 (en) | 2016-04-15 | 2017-10-19 | Generon (Shanghai) Corporation, Ltd. | Use of il-22 in treating necrotizing enterocolitis |
| CN112007146A (en) * | 2020-09-03 | 2020-12-01 | 上海市儿童医院 | Use of IL-22 in a medicament for the treatment and/or prevention of sepsis-induced liver injury |
| WO2022191828A1 (en) * | 2021-03-10 | 2022-09-15 | Wen Tan | NEW USE OF (R)-β2-AGONISTS IN TREATMENT OF SEPSIS AND ACUTE RESPIRATORY DISTRESS SYNDROME |
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| US20030003545A1 (en) * | 1998-05-29 | 2003-01-02 | Reinhard Ebner | Interleukins-21 and 22 |
| US20010023070A1 (en) * | 1998-05-29 | 2001-09-20 | Reinhard Ebner | Interleukins-21 and 22 |
| US7226591B2 (en) * | 2000-05-22 | 2007-06-05 | Genentech, Inc. | Interleukin-22 polypeptides, nucleic acids encoding the same and methods for the treatment of pancreatic disorders |
| US20050148029A1 (en) * | 2003-09-29 | 2005-07-07 | Biosite, Inc. | Methods and compositions for determining treatment regimens in systemic inflammatory response syndromes |
| CN100515491C (en) * | 2005-01-04 | 2009-07-22 | 健能隆医药技术（上海）有限公司 | Medical use of interleukin-22 |
| CN101219208B (en) * | 2005-01-04 | 2010-08-11 | 健能隆医药技术（上海）有限公司 | Medicine use of interleukin-22 |
| JP2009541338A (en) * | 2006-06-19 | 2009-11-26 | ワイス | Methods for modulating IL-22 and IL-17 |
| WO2008085229A2 (en) * | 2006-11-15 | 2008-07-17 | Arteriocyte Inc. | Cell-based therapies for treating liver disease |
| CN101168049A (en) * | 2007-10-23 | 2008-04-30 | 中国人民解放军军事医学科学院基础医学研究所 | Application of interleukin-22 in preparing medicine for treating hepatopathy and preparation method thereof |
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| EP2385841A1 (en) | 2011-11-16 |
| CA2748392A1 (en) | 2010-07-15 |
| EP2385841B1 (en) | 2016-11-16 |
| JP2012515165A (en) | 2012-07-05 |
| CN102348463B (en) | 2014-05-07 |
| US20110268696A1 (en) | 2011-11-03 |
| AU2010203446A1 (en) | 2011-07-14 |
| EP2385841A4 (en) | 2012-12-19 |
| WO2010081112A1 (en) | 2010-07-15 |
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